Guangdong Laboratory for Lingnan Modern Agriculture, National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, PR China.
Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics, Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, PR China.
Sci Adv. 2023 Jun 9;9(23):eadg4205. doi: 10.1126/sciadv.adg4205.
In the face of the alarming rise in global antimicrobial resistance, only a handful of novel antibiotics have been developed in recent decades, necessitating innovations in therapeutic strategies to fill the void of antibiotic discovery. Here, we established a screening platform mimicking the host milieu to select antibiotic adjuvants and found three catechol-type flavonoids-7,8-dihydroxyflavone, myricetin, and luteolin-prominently potentiating the efficacy of colistin. Further mechanistic analysis demonstrated that these flavonoids are able to disrupt bacterial iron homeostasis through converting ferric iron to ferrous form. The excessive intracellular ferrous iron modulated the membrane charge of bacteria via interfering the two-component system /, thereby promoting the colistin binding and subsequent membrane damage. The potentiation of these flavonoids was further confirmed in an in vivo infection model. Collectively, the current study provided three flavonoids as colistin adjuvant to replenish our arsenals for combating bacterial infections and shed the light on the bacterial iron signaling as a promising target for antibacterial therapies.
面对全球抗菌药物耐药性令人震惊的上升，近几十年来仅开发出少数几种新型抗生素，因此需要创新治疗策略来填补抗生素发现的空白。在这里，我们建立了一个模拟宿主环境的筛选平台，以选择抗生素佐剂，发现三种儿茶酚型类黄酮 - 7,8-二羟基黄酮、杨梅素和木樨草素 - 显著增强多粘菌素的疗效。进一步的机制分析表明，这些类黄酮能够通过将三价铁转化为二价形式来破坏细菌的铁稳态。过多的细胞内二价铁通过干扰双组分系统 / 来调节细菌的膜电荷，从而促进多粘菌素结合和随后的膜损伤。在体内感染模型中进一步证实了这些类黄酮的增效作用。总的来说，本研究提供了三种作为多粘菌素佐剂的类黄酮，为我们对抗细菌感染提供了更多的武器，并揭示了细菌铁信号作为抗菌治疗有前途的靶点。
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